Personalizing Depression Drugs

People diagnosed with clinical depression face a rough road to recovery. Many spend weeks, months, or even years trying different antidepressants in hopes of finding the right medication – one that cures their depression without insomnia, headaches, or other side effects.

Now two new kinds of genetic tests, one already available and one several years away, could help doctors and patients avoid this wearisome process.

“It’s very difficult to have to take a drug for weeks, then get off it and try a new one,” says Julio Licinio, a psychiatrist who studies the genetics of depression at the University of California, Los Angeles. “If we had any kind of marker that would tell us which person would respond to which drug, treatment would be much more efficient than it is now.”

Psychiatrists in the United States recently got a new set of tools to match the drug to the patient: genetic tests that can predict if a person will have side effects with a particular drug.

One such test, made by Swiss-based Roche Diagnostics, was approved by the U.S. Food and Drug Administration in January 2005 and was recently made available to doctors. The Roche test detects genetic variants for two enzymes involved in the break down of 25 percent of prescription drugs, including pain medications, beta-blockers, and antidepressants. Someone who has a form of the enzyme that breaks down a drug slowly is more likely to experience side effects at the standard dose because the drug builds up in the body. At the other extreme, someone who has a form of the enzyme that breaks down the drug very quickly may not have the medicine in the body long enough to do its job.

Experts predict that one of the major potential uses for the test will be in treating depression, because people react so variably to different antidepressants, and side effects are one of the main reasons people stop these drugs.

This test is one of the first attempts to take personalized medication to the clinic,” says Jose de Leon, a psychiatrist at the University of Kentucky in Lexington, who is studying the effectiveness of these tests. Specifically, he found that people with a mutation in one of these enzymes were more likely to stop taking the drug risperidone, an antipsychotic, because of adverse effects. He’s now working with Roche to see how efficient and cost effective the tests are in psychiatric hospitals.

While the test is commercially available, few doctors are using it yet. David Mrazek, chair of the psychiatry department at the Mayo Clinic in Rochester, MN, started using a version of the test in 2003, after studying it in his clinic. “As more clinicians understand the potential benefit, I think it will be used more,” says Mrazek.

The Roche test predicts who will experience side effects with a particular drug; but scientists are also searching for a trickier diagnostic: a genetic marker that can predict which drug will relieve depression most effectively in a particular patient.

Peter McGuffin, director of the Social, Genetic & Developmental Psychiatry Centre at the Institute of Psychiatry in London, is running a large, multicenter trial of 1,000 patients taking either citalopram, an antidepressant that acts on the neurotransmitter serotonin, or nortriptyline, which acts on the neurotransmitter norepinephrine.

Scientists are searching for genetic variations in the serotonin or norepinephrine pathways that predict how well a person responds to each drug. McGuffin and collaborators also plan to run a whole genome scan on each patient to search for genes outside these pathways that may also play a role in drug response to these two antidepressants. Experts say patients can expect to see tests derived from this type of trial in five to ten years.

Although the study is only partly completed, McGuffin has already had some success. His team confirmed that a variation in the gene for the serotonin transporter makes people less likely to respond to serotonin-based antidepressants.

Some drug companies are already starting to incorporate genetic testing into their drug development process. Clinical Data, a diagnostics and therapeutics company based in Newton, MA, announced plans this week for a clinical trial of a novel antidepressant that acts on the serotonin system. The drug failed earlier clinical trials; but Clinical Data researchers plan to develop a diagnostic test to identify a subset of people who do respond to the drug. If successful, the test would be marketed along with the drug.

Indeed, searching for genes that predict who will respond to a drug may actually be a more effective way to study depression than searching for genes that are implicated in the diseases itself, according to Steven Hamilton, a psychiatrist and geneticist at the University of California, San Francisco, who is involved in a large-scale study of depression in the United States. It is simpler, he says, to look for genes involved in drug response than at the complex genetic and environmental factors implicated in depression.

Caption for home page image: The AmpliChip CYP450 Test analyzes variations in two genes that play a major role in the metabolism of many widely prescribed drugs. Image courtesy of Roche Diagnostics.